The compound, which is the subject of the present invention [4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine] has the general formula (I):
and is described generically in EP 638 073.
EP 638 073 covers a group of trans isomers of 3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or 3-position of the piperazine ring. The compounds are described as having high affinity for dopamine D1, and D2receptors and the 5-HT2 receptor and are suggested to be useful for treatment of several diseases in the central nervous system, including schizophrenia. EP 638 073 does not disclose the specific enantiomeric form of the above compound of formula (I), only trans isomers in the form of racemates are described.
The enantiomer of formula (I) above has been described by Bøgesø et al. in J. Med. Chem., 1995, 38, page 4380-4392, in the form of the fumarate salt, see table 5, compound (−)-38. This publication concludes that the (−)-enantiomers of compound 38 is a potent D1/D2 antagonists showing some D1 selectivity in vitro while in vivo it is equipotent as D1 and D2 antagonist. The compound is also described as a potent 5-HT2 antagonist and as having high affinity for α1 adrenoceptors. It is also mentioned that the compound does not induce catalepsy in rats.
The corresponding racemate as well as the fumarate salt of the above compound of formula (I) is also described by Klaus P. Bøgesø in “Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds”, 1998, ISBN 87-88085-10-4 (cf. e.g. compound 69 in table 3, p47 and in table 9A, p101).
Thus, the compound of formula (I) is a mixed D1/D2 antagonists, a 5-HT2 antagonist and it has also affinity for α1 adrenoceptors. In the following is outlined the possible linkage between different diseases and the dopamine D1 and D2 receptors, the 5-HT2 receptors and the α1 adrenoceptors, respectively.
The aetiology of schizophrenia is not known, but the dopamine hypothesis of schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173), formulated in the early 1960s, has provided a theoretical framework for understanding the biological mechanisms underlying this disorder. In its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion which is supported by the fact that all antipsychotic drugs on the market today exert some dopamine D2 receptor antagonism (Seeman Science and Medicine 1995, 2, 28-37). However, whereas it is generally accepted that antagonism of dopamine D2 receptors in the limbic regions of the brain plays a key role in the treatment of positive symptoms of schizophrenia, the blockade of D2 receptors in striatal regions of the brain causes extrapyramidal symptoms (EPS). As described in EP 638 073 a profile of mixed dopamine D1/D2 receptor inhibition has been observed with some so-called “atypical” antipsychotic compounds, in particular with clozapine, used in treatment of schizophrenic patients.
Central α1 antagonistic actions has also been suggested to contribute in improving antipsychotic properties (Millan et al, JPET, 2000, 292, 38-53).
Further, selective D1 antagonists have been connected to treatment of sleep disorders and alcohol abuse (D.N.Eder, Current Opinion in Investigational Drugs, 2002 3(2):284-288).
Dopamine may also play an important role in the etiology of affective disorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-224, 225-236 and 237-246; J. Med. Chem., 1985, 28, 1817-1828).
In EP 638 073 is described how compounds having affinity for 5-HT2 receptors, in particular 5-HT2 receptors antagonists, have been suggested for treatment of different diseases, such as schizophrenia including the negative symptoms in schizophrenic patients, depression, anxiety, sleep disturbance, migraine attacks and neuroleptic-induced parkinsonism. 5-HT2 receptor antagonism has also been suggested to reduce the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).